Amyloid plaque aggregation inhibitors and diagnostic imaging agents

ABSTRACT

This invention relates to a method of imaging amyloid deposits and to labeled compounds, and methods of making labeled compounds useful in imaging amyloid deposits. This invention also relates to compounds, and methods of making compounds for inhibiting the aggregation of amyloid proteins to form-amyloid deposits, and a method of delivering a therapeutic agent to amyloid deposits.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of U.S. patent applicationSer. No. 10/127,678, filed Apr. 23, 2002, which claims the benefit ofU.S. Provisional Application No. 60/285,282, filed Apr. 23, 2001, thecontents of which are entirely incorporated by reference herein.

STATEMENT REGARDING FEDERALLY-SPONSORED RESEARCH AND DEVELOPMENT

[0002] Part of the work performed during development of this inventionutilized U.S. Government funds. The U.S. Government has certain rightsin this invention under grant numbers NS-18509 and PO1 AG-11542 awardedby the Institute for the Study of Aging.

BACKGROUND OF THE INVENTION

[0003] 1. Field of the Invention

[0004] This invention relates to novel bioactive compounds, methods ofdiagnostic imaging using radiolabeled compounds, and methods of makingradiolabeled compounds.

[0005] 2. Background Art

[0006] Alzheimer's disease (AD) is a progressive neurodegenerativedisorder characterized by cognitive decline, irreversible memory loss,disorientation, and language impairment. Postmortem examination of ADbrain sections reveals abundant senile plaques (SPs) composed ofamyloid-β (Aβ) peptides and numerous neurofibrillary tangles (NFTs)formed by filaments of highly phosphorylated tau proteins (for recentreviews and additional citations see Ginsberg, S. D., et al., “MolecularPathology of Alzheimer's Disease and Related Disorders,” in CerebralCortex: Neurodegenerative and Age-related Changes in Structure andFunction of Cerebral Cortex, Kluwer Academic/Plenum, NY (1999), pp.603-654; Vogelsberg-Ragaglia, V., et al., “Cell Biology of Tau andCytoskeletal Pathology in Alzheimer's Disease,” Alzheimer's Disease,Lippincot, Williams & Wilkins, Philadelphia, Pa. (1999), pp. 359-372).Familial AD (FAD) is caused by multiple mutations in the A precursorprotein (APP), presenilin 1 (PS1) and presenilin 2 (PS2) genes(Ginsberg, S. D., et al., “Molecular Pathology of Alzheimer's Diseaseand Related Disorders,” in Cerebral Cortex: Neurodegenerative andAge-related Changes in Structure and Function of Cerebral Cortex, KluwerAcademic/Plenum, NY (1999), pp. 603-654; Vogelsberg-Ragaglia, V., etal., “Cell Biology of Tau and Cytoskeletal Pathology in Alzheimer'sDisease,” Alzheimer's Disease, Lippincot, Williams & Wilkins,Philadelphia, Pa. (1999), pp. 359-372).

[0007] While the exact mechanisms underlying AD are not fullyunderstood, all pathogenic FAD mutations studied thus far increaseproduction of the more amyloidogenic 42-43 amino-acid long form of theAP peptide. Thus, at least in FAD, dysregulation of Aβ productionappears to be sufficient to induce a cascade of events leading toneurodegeneration. Indeed, the amyloid cascade hypothesis suggests thatformation of extracellular fibrillar Aβ aggregates in the brain may be apivotal event in AD pathogenesis (Selkoe, D. J., “Biology of B-amyloidPrecursor Protein and the Mechanism of Alzheimer's Disease,” Alzheimer'sDisease, Lippincot Williams & Wilkins, Philadelphia, Pa. (1999), pp.293-310; Selkoe, D. J., J. Am. Med. Assoc. 283:1615-1617 (2000);Naslund, J., et al., J. Am. Med. Assoc. 283:1571-1577 (2000); Golde, T.E., et al., Biochimica et Biophysica Acta 1502:172-187 (2000)).

[0008] Various approaches in trying to inhibit the production and reducethe accumulation of fibrillar Aβ in the brain are currently beingevaluated as potential therapies for AD (Skovronsky, D. M. and Lee, V.M., Trends Pharmacol. Sci. 21:161-163 (2000); Vassar, R., et al.,Science 286:735-741 (1999); Wolfe, M. S., et al., J. Med. Chem. 41:6-9(1998); Moore, C. L., et al., J. Med. Chem. 43:3434-3442 (2000);Findeis, M. A., Biochimica et Biophysica Acta 1502:76-84 (2000); Kuner,P., Bohrmann, et al., J. Biol. Chem. 275:1673-1678 (2000)). It istherefore of great interest to develop ligands that specifically bindfibrillar Aβ aggregates. Since extracellular SPs are accessible targets,these new ligands could be used as in vivo diagnostic tools and asprobes to visualize the progressive deposition of Aβ in studies of ADamyloidogenesis in living patients.

[0009] To this end, several interesting approaches for developingfibrillar AP aggregate-specific ligands have been reported (Ashburn, T.T., et al., Chem. Biol. 3:351-358 (1996); Han, G., et al., J. Am. Chem.Soc. 118:4506-4507 (1996); Klunk, W. E., et al., Biol. Psychiatry 35:627(1994); Klunk, W. E., et al., Neurobiol. Aging 16:541-548 (1995); Klunk,W. E., et al., Society for Neuroscience Abstract 23:1638 (1997); Mathis,C. A., et al., Proc. XIIth Intl. Symp. Radiopharm. Chem., Uppsala,Sweden:94-95 (1997); Lorenzo, A. and Yankner, B. A., Proc. Natl. Acad.Sci. U.S.A. 91:12243-12247 (1994); Zhen, W., et al., J. Med. Chem.42:2805-2815 (1999)). The most attractive approach is based on highlyconjugated chrysamine-G (CG) and Congo red (CR), and the latter has beenused for fluorescent staining of SPs and NFTs in postmortem AD brainsections (Ashburn, T. T., et al., Chem. Biol. 3:351-358 (1996); Klunk,W. E., et al., J. Histochem. Cytochem. 37:1273-1281 (1989)). Theinhibition constants (K′) for binding to fibrillar AP aggregates of CR,CG, and 3′-bromo- and 3′-iodo derivatives of CG are 2,800, 370, 300 and250 nM, respectively (Mathis, C. A., et al., Proc. XIIth Intl. Symp.Radiopharm. Chem., Uppsala, Sweden:94-95 (1997)). These compounds havebeen shown to bind selectively to Aβ (1-40) peptide aggregates in vitroas well as to fibrillar Aβ deposits in AD brain sections (Mathis, C. A.,et al., Proc. XIIth Intl. Symp. Radiopharm. Chem., Uppsala, Sweden:94-95(1997)).

[0010] Amyloidosis is a condition characterized by the accumulation ofvarious insoluble, fibrillar proteins in the tissues of a patient. Anamyloid deposit is formed by the aggregation of amyloid proteins,followed by the further combination of aggregates and/or amyloidproteins.

[0011] In addition to the role of amyloid deposits in Alzheimer'sdisease, the presence of amyloid deposits has been shown in diseasessuch as Mediterranean fever, Muckle-Wells syndrome, idiopatheticmyeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senileamyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage withamyloidosis, Down's syndrome, Scrapie, Creutzfeldt-Jacob disease, Kuru,Gerstamnn-Straussler-Scheinker syndrome, medullary carcinoma of thethyroid, Isolated atrial amyloid, β₂-microglobulin amyloid in dialysispatients, inclusion body myositis, β₂-amyloid deposits in muscle wastingdisease, and Islets of Langerhans diabetes Type II insulinoma.

[0012] Thus, a simple, noninvasive method for detecting and quantitatingamyloid deposits in a patient has been eagerly sought. Presently,detection of amyloid deposits involves histological analysis of biopsyor autopsy materials. Both methods have drawbacks. For example, anautopsy can only be used for a postmortem diagnosis.

[0013] The direct imaging of amyloid deposits in vivo is difficult, asthe deposits have many of the same physical properties (e.g., densityand water content) as normal tissues. Attempts to image amyloid depositsusing magnetic resonance imaging (MRI) and computer-assisted tomography(CAT) have been disappointing and have detected amyloid deposits onlyunder certain favorable conditions. In addition, efforts to labelamyloid deposits with antibodies, serum amyloid P protein, or otherprobe molecules have provided some selectivity on the periphery oftissues, but have provided for poor imaging of tissue interiors.

[0014] Potential ligands for detecting Aβ aggregates in the living brainmust cross the intact blood-brain barrier. Thus brain uptake can beimproved by using ligands with relatively smaller molecular size(compared to Congo Red) and increased lipophilicity. Highly conjugatedthioflavins (S and T) are commonly used as dyes for staining the Aβaggregates in the AD brain (Elhaddaoui, A., et al., Biospectroscopy 1:351-356 (1995)). These compounds are based on benzothiazole, which isrelatively small in molecular size. However, thioflavins contain anionic quarternary amine, which is permanently charged and unfavorablefor brain uptake.

[0015] Thus, it would be useful to have a noninvasive technique forimaging and quantitating amyloid deposits in a patient. In addition, itwould be useful to have compounds that inhibit the aggregation ofamyloid proteins to form amyloid deposits and a method for determining acompound's ability to inhibit amyloid protein aggregation.

BRIEF SUMMARY OF THE INVENTION

[0016] The present invention provides novel compounds of Formula I, II,III or III′ that bind preferentially to amyloid aggregates.

[0017] The present invention also provides diagnostic compositionscomprising a radiolabeled compound of Formula I, II, III or III′, and apharmaceutically acceptable carrier or diluent.

[0018] The invention further provides a method of imaging amyloiddeposits, the method comprising introducing into a patient a detectablequantity of a labeled compound of Formula I, II, III or III′ or apharmaceutically acceptable salt, ester, amide, or prodrug thereof.

[0019] The present invention also provides a method for inhibiting theaggregation of amyloid proteins, the method comprising administering toa mammal an amyloid inhibiting amount of a compound Formula I, II, IIIor III′ or a pharmaceutically acceptable salt, ester, amide, or prodrugthereof.

[0020] A further aspect of this invention is directed to methods andintermediates useful for synthesizing the amyloid inhibiting and imagingcompounds of Formula I, II, III or III′ described herein.

BRIEF DESCRIPTION OF THE FIGURE

[0021]FIG. 1A and FIG. 1B depict representative compounds of the presentinvention and the binding data for these compounds.

DETAILED DESCRIPTION OF THE INVENTION

[0022] A first aspect of the present invention is directed to compoundsof the following Formula I:

[0023] or a pharmaceutically acceptable salt thereof, wherein:

[0024] Y is CH, NR⁵, O, S or CH═N, where R⁵ is hydrogen or a C₁₋₄ alkyl;

[0025] m and n are both zero, or m and n are both 1;

[0026] R³ is CH₃, Br, I, F, ¹²⁵I, ¹³¹I, ¹²³I, ¹⁸F, ⁷⁶Br, ⁷⁷Br orSn(alkyl)₃;

[0027] R¹ and R² are independently hydrogen, C₁₋₄ alkyl, C₂₋₄aminoalkyl, C₁₋₄ haloalkyl, haloarylalkyl, -L-Ch, or R¹ and R² are takentogether with the nitrogen to which they are attached to form a 5- to7-member heterocyclic ring optionally having O, S or NR⁶ in said ring,where

[0028] R⁶ is hydrogen or C₁₋₄ alkyl; and

[0029] R⁴ is C₁₋₄ alkyl; and

[0030] L is a covalent bond or a linking group, such as —(CH₂)_(n)—, or—(CH₂), —C(O)— where n is 1-5; and

[0031] Ch is a tetradentate ligand capable of complexing with a metal,such as a ligand selected from the group consisting of:

[0032] where R⁹ is hydrogen or a sulfur protecting group, such asmethoxymethyl, methoxyethoxymethyl, p-methoxybenzyl or benzyl, and theother variable groups have the preferred values mentioned herein.

[0033] In this embodiment, compounds having Ch ligands, such as those ofFormulae VIII, IX, X and XI are complexed with 99m-pertechnetate, asdescribed herein to form metal chelates where Ch is selected from thegroup consisting of:

[0034] Additionally, a rhenium radioisotope can be complexed with the Chligand.

[0035] A preferred group of compounds falling within the scope of thepresent invention include compounds of Formula I wherein Y is selectedfrom NR′, O or S. Especially preferred compounds of Formula I includecompounds wherein Y is NR⁵ or S, most preferably Y is S.

[0036] Preferred values of R⁵ in compounds of Formula I where Y is NR⁵are hydrogen and C₁₋₄ alkyl, more preferably R⁵ is hydrogen or methyl,and most preferably R⁵ is hydrogen.

[0037] A preferred value of m and n in compounds of Formula I is fromzero to one, more preferably zero.

[0038] Suitable values of R³ are Br, I, F, ¹²⁵I, ¹³¹I, ¹²³I, ¹⁸F, ⁷⁶Br,or ⁷⁷Br. Especially useful values of R³ are ¹²⁵I, ¹³¹I, ¹²³I, ¹⁸F, ⁷⁶Br,or ⁷⁷Br, more preferably ¹²³I, ¹³¹I, ⁷⁶Br or ⁷⁷Br, and most preferably¹²³I. Preferred embodiments also include intermediates useful in thepreparation of compounds of Formula I wherein R³ is Sn(alkyl)₃.

[0039] Preferred compounds are those of Formula I wherein R¹ and R² areindependently one of hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl,halophenyl(C₁₋₄)alkyl, or are taken together with the nitrogen to whichthey are attached to form a 5- to 7-member heterocyclic ring optionallyhaving O or NR⁶ in said ring, where R⁶ is hydrogen or C₁₋₄ alkyl. Usefulvalues of R¹ and R² include, independently, hydrogen, methyl, ethyl,propyl, isopropyl, butyl, t-butyl, isobutyl, 3-fluoropropyl,4-fluorobutyl, or 4-fluorobenzyl, or R¹ and R² are taken together withthe nitrogen to which they are attached to form a piperidinyl ringhaving NR⁶ in said ring, where R⁶ is hydrogen or methyl.

[0040] The present invention is also directed to compounds of FormulaII:

[0041] or a pharmaceutically acceptable salt thereof, wherein:

[0042] Y is O or NR⁴ where R⁴ is hydrogen or C₁₋₄ alkyl;

[0043] R³ is Br, I, F, ¹²⁵I, ¹³¹I, ¹²³I, ¹⁸F, ⁷⁶Br, ⁷⁷Br or Sn(alkyl)₃;

[0044] R¹ and R² are independently hydrogen, C₁₋₄ alkyl, C₂₋₄aminoalkyl, C₁₋₄ haloalkyl, haloarylalkyl, or R¹ and R² are takentogether with the nitrogen to which they are attached to form a 5- to7-member heterocyclic ring optionally having O, S or NR⁵ in said ring,where

[0045] R⁵ is hydrogen or C₁₋₄ alkyl.

[0046] A preferred group of compounds include compounds of Formula IIwhere Y is NR⁴ where R⁴ is hydrogen or methyl. More preferred compoundsinclude compounds where Y is 0.

[0047] Useful values of R³ are Br, I, F, ¹²⁵I, ¹³¹I, ¹²³I, ¹⁸F, ⁷⁶Br, or⁷⁷Br. Especially suitable values of R³ are ¹²⁵I, ¹³¹I, ¹²³I, ¹⁸F, ⁷⁶Br,or ⁷⁷Br, more preferably ¹²³I, ¹³¹I, ⁷⁶Br or ⁷⁷Br, and most preferably¹²³I. Preferred embodiments also include intermediates useful in thepreparation of compounds of Formula II wherein R³ is Sn(alkyl)₃.

[0048] Preferred compounds are those of Formula II wherein R¹ and R² areindependently one of hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl,halophenyl(C₁₋₄)alkyl, or are taken together with the nitrogen to whichthey are attached to form a 5- to 7-member heterocyclic ring optionallyhaving O or NR⁶ in said ring, where R⁶ is hydrogen or C₁₋₄ alkyl. Usefulvalues of R¹ and R² include, independently, hydrogen, methyl, ethyl,propyl, butyl, t-butyl, isobutyl, 3-fluoropropyl, 4-fluorobutyl, or4-fluorobenzyl, or R¹ and R² are taken together with the nitrogen towhich they are attached to form a piperidinyl ring having NR⁶ in saidring, where R⁶ is hydrogen or methyl.

[0049] The present invention is also directed to compounds of FormulaIII:

[0050] or a pharmaceutically acceptable salt thereof, wherein:

[0051] R³ is Br, I, F, ¹²⁵I, ¹³¹I, ¹²³I, ¹⁸F, ⁷⁶Br, ⁷⁷Br or Sn(alkyl)₃;

[0052] R¹ and R² are independently hydrogen, C₁₋₄ alkyl, C₂₋₄aminoalkyl, C₁₋₄ haloalkyl, haloarylalkyl, -L-Ch, or R¹ and R² are takentogether with the nitrogen to which they are attached to form a 5- to7-member heterocyclic ring optionally having O, S or NR⁵ in said ring,where

[0053] R⁵ is hydrogen or C₄ alkyl.

[0054] Useful values of R³ are Br, I, F, ¹²⁵I, ¹³¹I, ¹²³I, ¹⁸F, ⁷⁶Br, or⁷⁷Br. Especially suitable values of R³ are ¹²⁵I, ¹³¹I, ¹²³I, ¹⁸F, ⁷⁶Br,or ⁷⁷Br, more preferably ¹²³I, ¹³¹I, ⁷⁶Br or ⁷⁷Br, and most preferably¹²³I or ¹²⁵I. Preferred embodiments also include intermediates useful inthe preparation of compounds of Formula III wherein R³ is Sn(alkyl)₃.

[0055] Preferred compounds are those of Formula III wherein R¹ and R²are independently one of hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl,halophenyl(C₁₋₄)alkyl, or are taken together with the nitrogen to whichthey are attached to form a 5- to 7-member heterocyclic ring optionallyhaving O or NR⁶ in said ring, where R⁶ is hydrogen or C₁₋₄ alkyl. Usefulvalues of R¹ and R² include, independently, hydrogen, methyl, ethyl,propyl, butyl, t-butyl, isobutyl, 3-fluoropropyl, 4-fluorobutyl, or4-fluorobenzyl, or R¹ and R² are taken together with the nitrogen towhich they are attached to form a piperidinyl ring having NR⁶ in saidring, where R⁶ is hydrogen or methyl. Most preferably R¹ and R² aremethyl.

[0056] Another preferred group of compounds are compounds of Formulae I,II, or III where R¹ is -L-Ch, R² is hydrogen or methyl, and R³ is I ormethyl. A preferred Ch is Formula IV. A preferred L is —(CH₂)_(n)— wheren

[0057] is 1, 2 or 3.

[0058] In a separate embodiment, compounds of Formula III have R¹ and R²groups as defined above, and R³ is -L-Ch, where L and Ch are as definedabove.

[0059] In another embodiment, the invention is directed to compounds ofFormula III′:

[0060] or a pharmaceutically acceptable salt thereof, wherein:

[0061] A, B and D are CH or N, provided that no more than two of A, Band D is N;

[0062] R³ is Br, I, F, ¹²⁵I, ¹³¹I, ¹²³I, ¹⁸F, ⁷⁶Br, ⁷⁷Br, haloalkyl orSn(alkyl)₃;

[0063] R¹ and R² are independently hydrogen, C₁₋₄ alkyl, C₂₋₄aminoalkyl, C₁₋₄ haloalkyl, haloarylalkyl, -L-Ch, or R¹ and R² are takentogether with the nitrogen to which they are attached to form a 5- to7-member heterocyclic ring optionally having O, S or NR⁵ in said ring,where

[0064] R⁵ is hydrogen or C₁₋₄ alkyl.

[0065] Useful values of R³ are Br, I, F, ¹²⁵I, ¹³¹I, ¹²³I, ¹⁸F, ⁷⁶Br,⁷⁷Br or ¹⁸F/fluoro(C₁₋₅) alkyl. Especially suitable values of R³ are¹⁸F/fluoromethyl, ¹⁸F/fluoroethyl, ¹⁸F/fluoropropyl, ¹⁸F/fluorobutyl, or¹⁸F/fluoropentyl. Preferred embodiments also include intermediatesuseful in the preparation of compounds of Formula III′ wherein R³ isSn(alkyl)₃.

[0066] In a preferred group of compounds, A and B are CH, and D is N. Inanother preferred group of compounds, A and D are CH, and B is N. Inanother preferred group of compounds, B and D are CH, and A is N.

[0067] Preferred compounds are those of Formula III′ wherein R¹ and R²are independently one of hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl,halophenyl(C₁₋₄)alkyl, or are taken together with the nitrogen to whichthey are attached to form a 5- to 7-member heterocyclic ring optionallyhaving O or NR⁶ in said ring, where R⁶ is hydrogen or C₁₋₄ alkyl. Usefulvalues of R¹ and R² include, independently, hydrogen, methyl, ethyl,propyl, butyl, t-butyl, isobutyl, 3-fluoropropyl, 4-fluorobutyl, or4-fluorobenzyl, or R¹ and R² are taken together with the nitrogen towhich they are attached to form a piperidinyl ring having NR⁶ in saidring, where R⁶ is hydrogen or methyl. Most preferably R¹ and R² aremethyl.

[0068] Another preferred group of compounds are compounds of Formula I,II, III or III′ where R¹ is -L-Ch, R² is hydrogen or methyl, and R³ is 1or methyl. A preferred Ch is Formula IV. A preferred L is —(CH₂)_(n)—where n is 1, 2 or 3.

[0069] In a separate embodiment, compounds of Formula III′ have R¹ andR² groups as defined above, and R³ is -L-Ch, where L is a covalent bondor linking group, such as —(CH₂)_(n)—, or —(CH₂)_(n)—C(O)— where n is0-5, and Ch is a tetradentate ligand capable of complexing with a metalas defined above. Most preferably, L is —(CH₂)_(n)—, where n is O, Ch isFormula XI, and R¹ and R² are independently hydrogen or C₁₋₄ alkyl. Inthis embodiment, it is most preferable that R¹ and R² are both methyl.

[0070] It is also to be understood that the present invention isconsidered to include stereoisomers as well as optical isomers, e.g.mixtures of enantiomers as well as individual enantiomers anddiastereomers, which arise as a consequence of structural asymmetry inselected compounds of the present series.

[0071] The compounds of Formula I, II, III, or III′ may also besolvated, especially hydrated. Hydration may occur during manufacturingof the compounds or compositions comprising the compounds, or thehydration may occur over time due to the hygroscopic nature of thecompounds. In addition, the compounds of the present invention can existin unsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

[0072] When any variable occurs more than one time in any constituent orin Formula I, II, III or III′, its definition on each occurrence isindependent of its definition at every other occurrence. Alsocombinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

[0073] Another aspect of this invention is related to methods ofpreparing compounds of Formula I, II, III or III′. A first method ischaracterized by forming a benzothiazole of Formula I wherein Y is S byreacting a 2-aminothiophenol with either: a) a 4-aminobenzaldehyde inDMSO at a temperature in the range of 100° C.-220° C., and collectingsaid benzothiazole; or b) a 4-halobenzoic acid derivative in a solventin the presence of polyphosphoric acid, collecting the product of thisreaction, followed by reacting said product with an amine to form saidbenzothiazole, and collecting said benzothiazole; and optionallyreacting a benzothiazole of Formula I wherein Y is S with (alkyl)₃Sn ina solvent in the presence of palladiumIIoxide to form a trialkylstannylbenzothiazole, and collecting the product of this reaction; andoptionally reacting a trialkylstannyl benzothiazole of Formula I whereinY is S with either: a) iodine in a solvent at ambient temperature, andextracting the product; or b) NaI or Na[¹²⁵I]I in the presence ofhydrogen peroxide, and extracting the product.

[0074] A second method is characterized by forming a benzoxazole ofFormula I wherein Y is O by reacting a 2-amino-5-nitrophenol with a4-aminobenzoic acid to form a nitro-substituted benzoxazoleintermediate, and collecting said intermediate; followed by catalytichydrogenation of said nitro group to an amino group, and collecting theproduct of this reaction; and reacting said product with NaNO₂ in thepresence of H⁺ and potassium halide to produce a benzoxazole of FormulaI wherein Y is O; and optionally reacting a benzoxazole of Formula Iwherein Y is O with (alkyl)₃Sn in a solvent in the presence ofpalladiumIIoxide to form a trialkylstannyl benzoxazole, and collectingthe product of this reaction; and optionally reacting a trialkylstannylbenzoxazole of Formula I wherein Y is O with either: a) iodine in asolvent at ambient temperature, and extracting the product; or b) NaI orNa[¹²⁵I]I in the presence of hydrogen peroxide, and extracting theproduct.

[0075] A third method is characterized by forming a benzimidazole ofFormula I wherein Y is N by reacting a 4-bromo-1,2-diaminobenzene witheither: a) a 4-aminobenzaldehyde to form a benzimidazole of Formula Iwherein Y is N, and collecting the product, or b) a 4-halobenzaldehydeto form an intermediate benzimidazole, and reacting said intermediatewith a monoalkylamine, dialkylamine, or heterocyclic amine in thepresence of palladiumIIoxide to form a benzimidazole of Formula Iwherein Y is N, and collecting the product; and optionally reacting abenzimidazole of Formula I wherein Y is N with (alkyl)₃Sn in a solventin the presence of palladiumIIoxide to form a trialkylstannylbenzimidazole, and collecting the product of this reaction; andoptionally reacting a trialkylstannyl benzimidazole of Formula I whereinY is N with either: a) iodine in a solvent at ambient temperature, andextracting the product; or b) NaI or Na[¹²⁵I]I in the presence ofhydrogen peroxide, and extracting the product.

[0076] A fourth method is characterized by forming a compound of FormulaI wherein R¹ or R² is -L-Ch. In embodiments where R¹ or R² is -L-Ch, thegroups R⁹ are both hydrogen, or can be any of the variety of protectinggroups available for sulfur, including methoxymethyl,methoxyethoxymethyl, p-methoxybenzyl or benzyl. Sulfur protecting groupsare described in detail in Greene, T. W. and Wuts, P. G. M., ProtectiveGroups in Organic Synthesis, 2nd Edition, John Wiley and Sons, Inc., NewYork (1991). Protecting group R⁹ can be removed by appropriate methodswell known in the art of organic synthesis, such as trifluoroaceticacid, mercuric chloride or sodium in liquid ammonia. In the case ofLewis acid labile groups, including acetamidomethyl and benzamidomethyl,R⁹ can be left intact. Labeling of the ligand with technetium in thiscase will cleave the protecting group, rendering the protecteddiaminedithiol equivalent to the unprotected form.

[0077] Tc-99m complexes can be prepared as follows. A small amount ofnon-radiolabeled compound (1-2 mg) is dissolved in 100 μL EtOH and mixedwith 200 μL HCl (1 N) and 1 mL Sn-glucoheptonate solution (containing8-32 μg SnCl₂ and 80-320 μg Na-glucoheptonate, pH 6.67) and 50 μL EDTAsolution (0.1 N). [^(99m)Tc]Pertechnetate (100-200 μL; ranging from 2-20mCi) saline solution are then added. The reaction is heated for 30 minat 100° C., then cooled to room temperature. The reaction mixture isanalyzed on TLC (EtOH:conc. NH₃ 9:1) for product formation and puritycheck. The mixture can be neutralized with phosphate buffer to pH 5.0.

[0078] The present invention further relates to a method of preparing atechnetium-99m complex according to the present invention by reactingtechnetium-99m in the form of a pertechnetate in the presence of areducing agent and optionally a suitable chelator with an appropriateCh-containing compound.

[0079] The reducing agent serves to reduce the Tc-99m pertechnetatewhich is eluted from a molybdenum-technetium generator in aphysiological saline solution. Suitable reducing agents are, forexample, dithionite, formamidine sulphinic acid, diaminoethanedisulphinate or suitable metallic reducing agents such as Sn(II),Fe(II), Cu(I), Ti(III) or Sb(III). Sn(II) has proven to be particularlysuitable.

[0080] For the above-mentioned complex-forming reaction, technetium-99mis reacted with an appropriate compound of the invention as a salt or inthe form of technetium bound to comparatively weak chelators. In thelatter case the desired technetium-99m complex is formed by ligandexchange. Examples of suitable chelators for the radionuclide aredicarboxylic acids, such as oxalic acid, malonic acid, succinic acid,maleic acid, orthophtalic acid, malic acid, lactic acid, tartaric acid,citric acid, ascorbic acid, salicylic acid or derivatives of theseacids; phosphorus compounds such as pyrophosphates; or enolates. Citricacid, tartaric acid, ascorbic acid, glucoheptonic acid or a derivativethereof are particularly suitable chelators for this purpose, because achelate of technetium-99m with one of these chelators undergoes thedesired ligand exchange particularly easily.

[0081] The most commonly used procedure for preparing [Tc^(v)O]⁺³N₂S₂complexes is based on stannous (II) chloride reduction of[^(99m)Tc]pertechnetate, the common starting material. The labelingprocedure normally relies on a Tc-99m ligand exchange reaction betweenTc-99m (Sn)-glucoheptonate and the N₂S₂ ligand. Preparation of stannous(II) chloride and preserving it in a consistent stannous (II) form iscritically important for the success of the labeling reaction. Tostabilize the air-sensitive stannous ion it is a common practice innuclear medicine to use a lyophilized kit, in which the stannous ion isin a lyophilized powder form mixed with an excess amount ofglucoheptonate under an inert gas like nitrogen or argon. Thepreparation of the lyophilized stannous chloride/sodium glucoheptonatekits ensures that the labeling reaction is reproducible and predictable.The N₂S₂ ligands are usually air-sensitive (thiols are easily oxidizedby air) and there are subsequent reactions which lead to decompositionof the ligands. The most convenient and predictable method to preservethe ligands is to produce lyophilized kits containing 100-500 μg of theligands under argon or nitrogen.

[0082] A fifth method is characterized by forming an isoxazole ofFormula II wherein Y is O by reacting a 3-halo-2-hydroxy benzaldehydewith a substituted benzamine such as 4-(halomethyl)-benzamine to form aphenoxy benzyl ether intermediate, and collecting the intermediate;followed by reacting said intermediate in a solvent in the presence ofNaOMe or NaOEt to form an isoxazole of Formula II wherein Y is O, andcollecting the product; and optionally reacting an isoxazole of FormulaI wherein Y is O with (alkyl)₃Sn in a solvent in the presence ofpalladiumIIoxide to form a trialkylstannyl isoxazole of Formula Iwherein Y is O, and collecting the product of this reaction; andoptionally reacting a trialkylstannyl isoxazole of Formula I wherein Yis O with either: a) iodine in a solvent at ambient temperature, andextracting the product; or b) NaI or Na[¹²⁵I]I in the presence ofhydrogen peroxide, and extracting the product.

[0083] A sixth method is characterized by forming an indole of FormulaII wherein Y is NR⁵ by reacting a 2-nitro-4-bromo toluene withN-isopropyl-2,2′-iminodiethanol to form aN,N-dimethyl-styryl-2-nitro-4-bromo benzene intermediate, followed byreacting said intermediate with an acid chloride in the presence oftriethylamine to produce an α,β-unsaturated ketone, which undergoesintramolecular annulation by heating in dioxane/water, followed byreacting with sodium hydrosulfite to form an indole of Formula IIwherein Y is NR⁴, and collecting the product; and optionally reactingsaid indole with methyl iodide in the presence of sodium hydride toproduce an indole of Formula II wherein Y is NR⁴ where R⁴ is methyl, andcollecting the product; and optionally reacting an indole of Formula IIwherein Y is NR¹ with (alkyl)₃Sn in a solvent in the presence ofpalladiumIIoxide to form a trialkylstannyl indole of Formula II whereinY is NR⁴, and collecting the product of this reaction; and optionallyreacting a trialkylstannyl indole of Formula II wherein Y is NR⁴ witheither: a) iodine in a solvent at ambient temperature, and extractingthe product; or b) NaI or Na[¹²⁵I]I in the presence of hydrogenperoxide, and extracting the product.

[0084] A seventh method characterized by forming animidazo[1,2a]pyridine of Formula III by reacting2-amino-5-bromo-pyridine with either: a) a 4′-halo-1-halo-benzophenonein a solvent in the presence of sodium bicarbonate to form anintermediate imidazo[1,2a]pyridine, and collecting the product of thereaction; followed by reacting said intermediate with a monoalkylamine,dialkylamine or heterocyclic amine in the presence of palladiumIIoxideto form an imidazo[1,2a]pyridine of Formula III, or b) a4′-amino-1-halo-acetophenone in a solvent in the presence of sodiumbicarbonate to form an imidazo[1,2a]pyridine of Formula III, andcollecting the product of the reaction; and optionally reacting animidazo[1,2a]pyridine of Formula III with (alkyl)₃Sn in a solvent in thepresence of palladiumIIoxide to form a trialkylstannylimidazo[1,2a]pyridine of Formula III, and collecting the product of thisreaction; and optionally reacting a trialkylstannylimidazo[1,2a]pyridine of Formula III with either: a) iodine in a solventat ambient temperature, and extracting the product; or b) NaI orNa[¹²⁵I]I in the presence of hydrogen peroxide, and extracting theproduct.

[0085] The term “alkyl” as employed herein by itself or as part ofanother group refers to both straight and branched chain radicals of upto 8 carbons, preferably 6 carbons, more preferably 4 carbons, such asmethyl, ethyl, propyl, isopropyl, butyl, t-butyl, and isobutyl.

[0086] The term “alkoxy” is used herein to mean a straight or branchedchain alkyl radical, as defined above, unless the chain length islimited thereto, bonded to an oxygen atom, including, but not limitedto, methoxy, ethoxy, n-propoxy, isopropoxy, and the like. Preferably thealkoxy chain is 1 to 6 carbon atoms in length, more preferably 1-4carbon atoms in length.

[0087] The term “monoalkylamine” as employed herein by itself or as partof another group refers to an amino group which is substituted with onealkyl group as defined above.

[0088] The term “dialkylamine” as employed herein by itself or as partof another group refers to an amino group which is substituted with twoalkyl groups as defined above.

[0089] The term “halo” employed herein by itself or as part of anothergroup refers to chlorine, bromine, fluorine or iodine.

[0090] The term “aryl” as employed herein by itself or as part ofanother group refers to monocyclic or bicyclic aromatic groupscontaining from 6 to 12 carbons in the ring portion, preferably 6-10carbons in the ring portion, such as phenyl, naphthyl ortetrahydronaphthyl.

[0091] The term “heterocycle” or “heterocyclic ring”, as used hereinexcept where noted, represents a stable 5- to 7-memeberedmono-heterocyclic ring system which may be saturated or unsaturated, andwhich consists of carbon atoms and from one to three heteroatomsselected from the group consisting of N, O, and S, and wherein thenitrogen and sulfur heteroatom may optionally be oxidized. Especiallyuseful are rings contain one nitrogen combined with one oxygen orsulfur, or two nitrogen heteroatoms. Examples of such heterocyclicgroups include piperidinyl, pyrrolyl, pyrrolidinyl, imidazolyl,imidazlinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl,oxazolidinyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolidinyl,isothiazolyl, homopiperidinyl, homopiperazinyl, pyridazinyl, pyrazolyl,and pyrazolidinyl, most preferably thiamorpholinyl, piperazinyl, andmorpholinyl.

[0092] The term “heteroatom” is used herein to mean an oxygen atom(“O”), a sulfur atom (“S”) or a nitrogen atom (“N”). It will berecognized that when the heteroatom is nitrogen, it may form anNR^(a)R^(b) moiety, wherein R^(a) and R^(b) are, independently from oneanother, hydrogen or C₁₋₄ alkyl, C₂₋₄ aminoalkyl, C₁₋₄ halo alkyl, halobenzyl, or R¹ and R² are taken together to form a 5- to 7-memberheterocyclic ring optionally having O, S or NR^(c) in said ring, whereR^(c) is hydrogen or C₁₋₄alkyl.

[0093] The present invention is further directed to a methods ofpreparing compounds of the above Formula I, II III or III′. Thecompounds of this invention can be prepared by reactions described inSchemes 1-13.

[0094] Schemes 1 and 2 depict a synthetic route for formingbenzothiazoles of Formula I. Heating 5-bromo-2-amino-benzenethiol(Mital, R. L. and Jain, S. K., J Chem Soc (C):2148 (1969); Lin, A. -J.and Kasina, S., J Heterocycl Chem 18:759 (1981)) and4-dimethylaminobenzaldehyde or 4-(4-methylpiperazin-1-yl) benzaldehyde(Tanaka, A., et al., J. Med. Chem. 41:2390 (1998)) in DMSO producedbenzothiazoles, 1 and 4. Using the same Pd(0)-catalyzed Br totributyltin exchange reaction, these two bromo derivatives weresuccessfully converted to the corresponding tributyltin derivatives 2and 5. They were successfully used in an iododestannylation reaction toproduce the corresponding iodinated compounds 3 and 6 (yields werebetween 25-35%; the reactions were not optimized). Thus, the tributyltinderivatives served two useful purposes, i) they served as intermediatesfor converting bromo to iodo derivatives; ii) they are also useful asstarting material for preparation of radioiodinated “hot” ligand.

[0095] Scheme 3 depicts a synthetic route in which N-monomethylatedamines are prepared, and thereafter employed in the parallel synthesisof disubstituted aminophenyl benzothiazole derivatives.

[0096] Schemes 4 through 6 depict synthetic routes for formingbenzoxazoles of the present invention.

[0097] Schemes 7, 8 and 9 depict synthetic routes for preparing indolederivatives and benzimidazole derivatives of the present invention.

[0098] Scheme 10 depicts a synthetic route for forming benzofuranderivatives of the present invention. Alternatively, benzofurans can beprepared via an intramolecular Wittig Route (Twyman, et al., TetrahedronLett 40:9383 (1999)) as set forth in Scheme 11.

[0099] Scheme 12 provides a synthetic route for parallel synthesis ofbenzofuran derivatives of the present invention.

[0100] Schemes 13 through 17 are directed to imidazo[1,2,a]pyridinederivatives of the present invention.

[0101] Schemes 18 and 19 depict synthetic routes for formingbenzopyrimidines of the present invention.

[0102] Scheme 20 depicts the synthesis of metal-chelated complexes ofthe present invention, where R⁹ is as defined above, and Ar is abicyclic system selected from the group comprising: benzothiazyl,benzoxazolyl, benzimidazolyl, benzofuranyl, imidazo[1,2a]pyridyl, andbenzopyrimidyl.

[0103] Shemes 21 through 23 are directed to imidazo[1,2a][1,3]diazepinederivatives of Formula III′.

[0104] When the compounds of this invention are to be used as imagingagents, they must be labeled with suitable radioactive halogen isotopes.Although ¹²⁵I-isotopes are useful for laboratory testing, they willgenerally not be useful for actual diagnostic purposes because of therelatively long half-life (60 days) and low gamma-emission (30-65 Kev)of ¹²⁵I. The isotope ¹²³I has a half life of thirteen hours and gammaenergy of 159 KeV, and it is therefore expected that labeling of ligandsto be used for diagnostic purposes would be with this isotope. Otherisotopes which may be used include ¹³¹I (half life of 2 hours). Suitablebromine isotopes include ⁷⁷Br and ⁷⁶Br.

[0105] The radiohalogenated compounds of this invention lend themselveseasily to formation from materials which could be provided to users inkits. Kits for forming the imaging agents can contain, for example, avial containing a physiologically suitable solution of an intermediateof Formula I, II, III or III′ in a concentration and at a pH suitablefor optimal complexing conditions. The user would add to the vial anappropriate quantity of the radioisotope, e.g., Na¹²³I, and an oxidant,such as hydrogen peroxide. The resulting labeled ligand may then beadministered intravenously to a patient, and receptors in the brainimaged by means of measuring the gamma ray or photo emissions therefrom.

[0106] Since the radiopharmaceutical composition according to thepresent invention can be prepared easily and simply, the preparation canbe carried out readily by the user. Therefore, the present inventionalso relates to a kit, comprising:

[0107] (1) A non-radiolabeled compound of the invention, the compoundoptionally being in a dry condition; and also optionally having aninert, pharmaceutically acceptable carrier and/or auxiliary substancesadded thereto; and

[0108] (2) a reducing agent and optionally a chelator;

[0109] wherein ingredients (1) and (2) may optionally be combined; and

[0110] further wherein instructions for use with a prescription forcarrying out the above-described method by reacting ingredients (1) and(2) with technetium-99m in the form of a pertechnetate solution may beoptionally included.

[0111] Examples of suitable reducing agents and chelators for the abovekit have been listed above. The pertechnetate solution can be obtainedby the user from a molybdenum-technetium generator. Such generators areavailable in a number of institutions that perform radiodiagnosticprocedures. As noted above the ingredients (1) and (2) may be combined,provided they are compatible. Such a monocomponent kit, in which thecombined ingredients are preferably lyophilized, is excellently suitableto be reacted by the user with the pertechnetate solution in a simplemanner.

[0112] When desired, the radioactive diagnostic agent may contain anyadditive such as pH controlling agents (e.g., acids, bases, buffers),stabilizers (e.g., ascorbic acid) or isotonizing agents (e.g., sodiumchloride).

[0113] The term “pharmaceutically acceptable salt” as used herein refersto those carboxylate salts or acid addition salts of the compounds ofthe present invention which are, within the scope of sound medicaljudgement, suitable for use in contact with the tissues of patientswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the invention. The term “salts” refers to therelatively nontoxic, inorganic and organic acid addition salts ofcompounds of the present invention. Also included are those saltsderived from non-toxic organic acids such as aliphatic mono anddicarboxylic acids, for example acetic acid, phenyl-substituted alkanoicacids, hydroxy alkanoic and alkanedioic acids, aromatic acids, andaliphatic and aromatic sulfonic acids. These salts can be prepared insitu during the final isolation and purification of the compounds or byseparately reacting the purified compound in its free base form with asuitable organic or inorganic acid and isolating the salt thus formed.Further representative salts include the hydrobromide, hydrochloride,sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate,palmitate, stearate, laurate, borate, benzoate, lactate, phosphate,tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylatemesylate, glucoheptonate, lactiobionate and laurylsulphonate salts,propionate, pivalate, cyclamate, isethionate, and the like. These mayinclude cations based on the alkali and alkaline earth metals, such assodium, lithium, potassium, calcium, magnesium, and the like, as wellas, nontoxic ammonium, quaternary ammonium and amine cations including,but not limited to ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine,and the like. (See, for example, Berge S. M., et al., PharmaceuticalSalts, J. Pharm. Sci. 66:1-19 (1977) which is incorporated herein byreference.)

[0114] In the first step of the present method of imaging, a labeledcompound of Formula I, II, III or III′ is introduced into a tissue or apatient in a detectable quantity. The compound is typically part of apharmaceutical composition and is administered to the tissue or thepatient by methods well known to those skilled in the art.

[0115] For example, the compound can be administered either orally,rectally, parenterally (intravenous, by intramuscularly orsubcutaneously), intracistemally, intravaginally, intraperitoneally,intravesically, locally (powders, ointments or drops), or as a buccal ornasal spray.

[0116] In a preferred embodiment of the invention, the labeled compoundis introduced into a patient in a detectable quantity and aftersufficient time has passed for the compound to become associated withamyloid deposits, the labeled compound is detected noninvasively insidethe patient. In another embodiment of the invention, a labeled compoundof Formula I, II, III or III′ is introduced into a patient, sufficienttime is allowed for the compound to become associated with amyloiddeposits, and then a sample of tissue from the patient is removed andthe labeled compound in the tissue is detected apart from the patient.In a third embodiment of the invention, a tissue sample is removed froma patient and a labeled compound of Formula I, II, III or III′ isintroduced into the tissue sample. After a sufficient amount of time forthe compound to become bound to amyloid deposits, the compound isdetected.

[0117] The administration of the labeled compound to a patient can be bya general or local administration route. For example, the labeledcompound maybe administered to the patient such that it is deliveredthroughout the body. Alternatively, the labeled compound can beadministered to a specific organ or tissue of interest. For example, itis desirable to locate and quantitate amyloid deposits in the brain inorder to diagnose or track the progress of Alzheimer's disease in apatient.

[0118] The term “tissue” means a part of a patient's body. Examples oftissues include the brain, heart, liver, blood vessels, and arteries. Adetectable quantity is a quantity of labeled compound necessary to bedetected by the detection method chosen. The amount of a labeledcompound to be introduced into a patient in order to provide fordetection can readily be determined by those skilled in the art. Forexample, increasing amounts of the labeled compound can be given to apatient until the compound is detected by the detection method ofchoice. A label is introduced into the compounds to provide fordetection of the compounds.

[0119] The term “patient” means humans and other animals. Those skilledin the art are also familiar with determining the amount of timesufficient for a compound to become associated with amyloid deposits.The amount of time necessary can easily be determined by introducing adetectable amount of a labeled compound of Formulae I-III′ into apatient and then detecting the labeled compound at various times afteradministration.

[0120] The term “associated” means a chemical interaction between thelabeled compound and the amyloid deposit. Examples of associationsinclude covalent bonds, ionic bonds, hydrophilic-hydrophilicinteractions, hydrophobic-hydrophobic interactions, and complexes.

[0121] Those skilled in the art are familiar with the various ways todetect labeled compounds. For example, magnetic resonance imaging (MRI),positron emission tomography (PET), or single photon emission computedtomography (SPECT) can be used to detect radiolabeled compounds. Thelabel that is introduced into the compound will depend on the detectionmethod desired. For example, if PET is selected as a detection method,the compound must possess a positron-emitting atom, such as ¹¹C or ¹⁸F.

[0122] The radioactive diagnostic agent should have sufficientradioactivity and radioactivity concentration which can assure reliablediagnosis. For instance, in case of the radioactive metal beingtechnetium-99m, it may be included usually in an amount of 0.1 to 50 mCiin about 0.5 to 5.0 ml at the time of administration. The amount of acompound of Formulae I-III′ may be such as sufficient to form a stablechelate compound with the radioactive metal.

[0123] The thus formed chelate compound as a radioactive diagnosticagent is sufficiently stable, and therefore it may be immediatelyadministered as such or stored until its use. When desired, theradioactive diagnostic agent may contain any additive such as pHcontrolling agents (e.g., acids, bases, buffers), stabilizers (e.g.,ascorbic acid) or isotonizing agents (e.g., sodium chloride).

[0124] The imaging of amyloid deposits can also be carried outquantitatively so that the amount of amyloid deposits can be determined.

[0125] Preferred compounds for imaging include a radioisotope such as¹²³I, ¹²⁵I, ¹³¹I, ¹⁸F, ⁷⁶Br or ⁷⁷Br.

[0126] The present invention is also directed at a method of imagingamyloid deposits. One of the key prerequisites for an in vivo imagingagent of the brain is the ability to cross the intact blood-brainbarrier after a bolus iv injection. The compounds of this inventionpossess a core ring system comprised of various substituted, fused 5-and 6-member aromatic rings. Several compounds of this invention containa benzothiazole core and are derivatives of thioflavins. These compoundscontain no quaternary ammonium ion, therefore, they are relatively smallin size, neutral and lipophilic (Partition Coefficient=70 and 312 for 3and 6a, respectively).

[0127] To test the permeability through the intact blood-brain barrierseveral compounds of Formula I or Emi were injected into normal mice.Initial brain uptake of 3 and 6a in mice after an iv injection was 0.67and 1.50% dose/organ, respectively (see Table 1). The brain uptakepeaked at 60 min for both compounds with a maximum brain uptake of 1.57and 1.89% dose/organ, respectively. The blood levels are relatively lowthroughout the time points evaluated. For this series of ligands,specific uptake in the brain is relatively high and the retention in thebrain is long.

[0128] Another aspect of the invention is a method of inhibiting amyloidplaque aggregation. The present invention also provides a method ofinhibiting the aggregation of amyloid proteins to form amyloid deposits,by administering to a patient an amyloid inhibiting amount of a compoundof the above Formula I, II,

[0129] Those skilled in the art are readily able to determine an amyloidinhibiting amount by simply administering a compound of Formula I, II,III or III′ to a patient in increasing amounts until the growth ofamyloid deposits is decreased or stopped. The rate of growth can beassessed using imaging as described above or by taking a tissue samplefrom a patient and observing the amyloid deposits therein. The compoundsof the present invention can be administered to a patient at dosagelevels in the range of about 0.1 to about 1,000 mg per day. For a normalhuman adult having a body weight of about 70 kg, a dosage in the rangeof about 0.01 to about 100 mg per kilogram of body weight per day issufficient. The specific dosage used, however, can vary. For example,the dosage can depend on a number of factors including the requirementsof the patient, the severity of the condition being treated, and thepharmacological activity of the compound being used. The determinationof optimum dosages for a particular patient is well known to thoseskilled in the art.

[0130] The following examples are illustrative, but not limiting, of themethod and compositions of the present invention. Other suitablemodifications and adaptations of the variety of conditions andparameters normally encountered and obvious to those skilled in the artare within the spirit and scope of the invention.

EXAMPLE 1 2-(4′-Dimethylaminophenyl)-6-iodobenzothiazole, (3)

[0131] 2-(4′-Dimethylaminophenyl)-6-bromobenzothiazole (1): (Stevens, M.F. G., et al., J. Med. Chem. 37:1689-1695 (1994); Stevens, M. F. G., etal., PCT Int. Appl. WO19940830:47 (1995))

[0132] A mixture of 5-bromo-2-amino-benzenethiol (Mital, R. L. and Jain,S. K., J. Chem Soc (C):2148 (1969); Lin, A. -J. and Kasina, S., JHeterocycl Chem 18:759 (1981)) (306 mg, 1.5 mmol) and 4-dimethylaminobenzaldehyde (224 mg, 1.5 mmol) in DMSO was heated at 180° C. for 15min. Water (10 mL) was added after the mixture was cooled down. Thesolid was collected by suction and recrystallized in ethyl acetate togive 340 mg of product (68%).

[0133]¹H NMR (200 MHz, CDCl₃): δ 3.06 (s, 6H), 6.74 (d, J=9.0 Hz, 2H),7.52 (d,d, J=8.7, 2.0 Hz, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.93 (d, J=8.8Hz, 2H), 7.95 (s,1H).

[0134] HRMS: m/z Calcd for C₁₅H₁₄BrN₂S(MH⁺): 333.0061; Found: 333.0072.

[0135] 2-(4′-Dimethylaminophenyl)-6-tribytylstannylbenzothiazole (2): Toa solution of 2-(4′-dimethylaminophenyl)-6-bromobenzothiazole (16a)(60mg, 0.18 mmol) in 1,4-dioxane (2 mL), toluene (2 mL) and triethylamine(2 mL) was added (Bu₃Sn)₂ (0.2 mL) followed by Pd(Ph₃P)₄ (20 mg). Themixture was stirred at 90° C. overnight. Solvent was removed and theresidue was purified by PTLC (Hex:EtOAc, 6:1) to give 33 mg of product(yield 33.6%).

[0136]¹H NMR (200 MHz, CDCl₃): δ 0.90 (t, J=7.1 Hz, 9H), 1.10 (t, J=8.0Hz, 6H), 1.34 (hex, J=7.3 Hz, 6H), 1.57 (m, 6H), 3.05 (s, 6H), 6.74 (d,J=9.0 Hz, 2H), 7.50 (d,d, J=7.9, 0.9 Hz, 1H), 7.93 (s,1H), 7.95 (d,J=8.5 Hz,1H), 7.97 (d, J=9.0 Hz, 2H).

[0137] HRMS: m/z Calcd for C₂₇H₄₁N₂SSn(MH⁺): 545.2012; Found: 545.2035.

[0138] 2-(4′-Dimethylaminophenyl)-6-iodobenzothiazole, (3): To asolution of 2 (45 mg, 0.08 mmol) in CHCl₃ (10 mL) was added a solutionof iodine (1 mL, 1M in CHCl₃) dropwise at RT until the color maintainingunchanged. The resulting mixture was stirred at RT for 10 min. NaHSO₃solution (2 mL, 5% in water) and KF (1 mL, 1M in MeOH) were addedsuccessively. The mixture was stirred for 5 min and the organic phasewas separated. The aqueous phase was extracted with CH₂Cl₂ and thecombined organic phases was dried over Na₂SO₄, filtered and concentratedto give crude product which was purified by PTLC (Hex:EtOAc, 6:1) togive 9 mg of the desired product (yield 29%). ¹HNMR (200 MHz, CDCl₃): δ3.06 (s, 6H), 6.73 (d, J=9.0 Hz, 2H), 7.69 (s, 1H), 7.70 (s, 1H), 7.93(d, J=9.0 Hz, 2H), 8.15 (s, 1H).

[0139] HRMS: m/z Calcd for C₁₅H₁₅N₂IS(MH⁺): 380.9922; Found: 380.9914.

[0140] Anal. (C₁₅H₁₄N₃IS): C, H, N.

EXAMPLE 2 2-[4′-(4″-Methylpiperazin-1-yl)-phenyl]-6-iodobenzothiazole,(6)

[0141] 2-[4′-(4″-Methylpiperazin-1-yl)-phenyl]-6-bromobenzothiazole (4):The procedure described above to prepare 1 was employed to give 57.2% ofproduct 4 from 4-(4-methylpiperazin-1-yl)benzaldehyde (Tanaka, A., etal., J. Med. Chem. 41:2390 (1998)) (204 mg, 1 mmol) and5-bromo-2-amino-benzenethiol (204 mg, 1 mmol).

[0142]¹H NMR (200 MHz, CDCl₃): δ 2.38 (s, 3H), 2.60 (t, J=5.0 Hz, 4H),3.38 (t, J=5.0 Hz, 4H), 6.96 (d, J=8.9 Hz, 2H), 7.54 (d,d, J=8.5, 1.9Hz, 1H), 7.83 (d, J=8.5 Hz,1H), 7.95 (d, J=8.9 Hz, 2H), 7.98 (s,1H).

[0143] HRMS: m/z Calcd for C₁₈H₁₉BrN₃S(MH⁺): 388.0483; Found: 388.0474.

[0144] 2-4′-(4″-Methylpiperazin-1-yl)-phenyl]-6-tributylstannylbenzothiazole (5): The procedure described above to prepare 2 wasemployed, 5 was obtained in 23% yield from 4.

[0145]¹H NMR (200 MHz, CDCl₃): δ 0.89 (t, J=7.2 Hz, 9H), 1.06 (t, J=8.2Hz, 6H), 1.30 (hex, J=7.3 Hz, 6H), 1.57 (pen, J=7.2 Hz, 6H), 2.38 (s,3H), 2.60 (m, 4H), 3.36 (t, J=5.0 Hz, 4H), 6.96 (d, J=8.9 Hz, 2H), 7.52(d, J=7.9 Hz, 1H), 7.93 (s,1H), 7.95 (d, J=7.9 Hz,1H), 7.98 (d, J=8.9Hz, 2H).

[0146] HRMS: m/z Calcd for C₃₀H₄₆N₃SSn(MH⁺): 600.2434; Found: 600.2449.

[0147] 2-[4′-(4″-Methylpiperazin-1-yl)-phenyl]-6-iodobenzothiazole, (6):The same reaction as described above to prepare 3 was employed, 6 wasobtained in 36% yield from 5.

[0148]¹H NMR (200 MHz, CDCl₃): δ 2.42 (s, 3H), 263 (t, J=4.8 Hz, 4H),3.40 (t, J=4.9 Hz, 4H), 6.95 (d, J=9.0 Hz, 2H), 7.71 (s,1H), 7.72(s,1H), 7.95 (d, J=8.9 Hz, 2H), 8.17 (t, J=1.0 Hz, 1H).HRMS: m/z Calcdfor C₁₈H₁₉N₃IS(MH⁺): 436.0344; Found: 436.0364. Anal. (C₁₈H₁₈N₃SI): C,H, N.

EXAMPLE 3 Preparation of6-Tributylstannyl-2-(4′-dimethylamino-)phenyl-imidazo[1,2a]pyridine (18)

[0149] 6-Bromo-2-(4′-dimethylamino-)phenyl-imidazo[1,2-a]pyridine (17)

[0150] A mixture of 2-bromo-4′-dimethylaminoacetophenone, (968 mg, 4mmol) and 2-amino-5-bromo-pyridine (692 mg, 4 mmol) in EtOH (25 mL) wasstirred under reflux for 2 hr. NaHCO3 (500 mg) was added after themixture was cooled down. The resulting mixture was stirred under refluxfor 4.5 hr. The mixture was cooled down, filtered to give 655 mg ofproduct, 17 (52%).

[0151]¹H NMR (200 MHz, CDCl₃,δ): 3.00 (s, 6H), 6.78 (d, J=8.7 Hz, 2H),7.17 (d,d, J=9.5, 1.7 Hz, 1H), 7.49 (d, J=9.5 Hz, 1H), 7.69 (s, 1H),7.80 (d, J=8.7 Hz, 2H), 8.21 (d,d, J=1.7, 0.8 Hz, 1H). Anal.3a,(C₁₅H₁₄BrN₃)

[0152]6-Tributylstannyl-2-(4′-dimethylamino-)phenyl-imidazo[1,2-a]pyridine(18).

[0153] To a solution of 6-bromo-2-(4′-dimethylamino-)phenyl-imidazo[1,2-a]pyridine, 17, (80 mg, 0.26 mmol) in 1,4-dioxane (10 mL) andtriethylamine (2 mL) was added (Bu3Sn)₂ (0.2 mL) in neat followed byPd(Ph3P)₄ (20 mg). The mixture was stirred at 90° C. overnight. Solventwas removed and the residue was purified by PTLC (Hex:EtOAc=1:1 asdeveloping solvent) to give 23 mg of product, 18 (17%).

[0154]¹H NMR (200 MHz, CDCl₃,δ): 0.90 (t, J=7.2 Hz, 9H), 1.10 (t, J=8.0Hz, 6H), 1.33 (hex, J=7.1 Hz, 6H), 1.54 (pen, J=7.2 Hz, 6H), 3.00 (s,6H), 6.78 (d, J=8.9 Hz, 2H), 7.11 (d, J=8.8 Hz, 1H), 7.57 (d, J=8.8 Hz,1H), 7.71 (s, 1H), 7.84 (d, J=8.8 Hz, 2H), 7.95 (d, J=0.8 Hz, 1H). HRMS:m/z Calcld for C₂₇H₄₂N₃Sn(M++H): 528.2400; Found: 528.2402. Anal.4,(C₂₇H₄₁N₃Sn.2H₂O)

[0155] 6-Iodo-2-(4′-dimethylamino-)phenyl-imidazo[1,2-a]pyridine, IMPY,(16)

[0156] A mixture of 2-bromo-4′-dimethylaminoacetophenone, (484 mg, 2mmol) and 2-amino-5-iodo-pyridine (440 mg, 2 mmol) in EtOH (25 mL) wasstirred under reflux for 2 hr. NaHCO3 (250 mg) was added after themixture was cooled down. The resulting mixture was stirred under refluxfor 4 hr. The mixture was cooled down, filtered to give 348 mg ofproduct, 3b (48%).

[0157]¹H NMR (200 MHz, CDCl₃,δ): 3.00 (s, 6H), 6.77 (d, J=8.8 Hz, 2H),7.27 (d,d, J=9.4, 1.5 Hz, 1H), 7.38 (d, J=9.5 Hz, 1H), 7.66 (s, 1H),7.79 (d, J=8.8 Hz, 2H), 8.32 (d, J=0.7 Hz, 1H). Anal.3b, (C₁₋₅H₄IN₃).

EXAMPLE 4 Preparation of Radioiodinated Ligand: [¹²⁵I]IMPY, [¹²⁵I]18

[0158] The compound, [¹²⁵I] 18, was prepared using iododestannylationreactions with tributyltin precursor 17. Hydrogen peroxide (50 μL, 3%w/v) was added to a mixture of 50 mL of the correspondent tributyltinprecursor (1 μg/μL EtOH), 50 mL of 1N HCl and [^(125/123)I]NaI (1-5 mCi)in a sealed vial. The reaction was allowed to proceed for 10 min at roomtemperature and terminated by addition of 100 mL of sat. NaHSO₃. Thereaction mixture was either directly extracted (styrylbenzenes) withethylacetate (3×1 mL) or extracted after neutralization with saturatedsodium bicarbonate solution (thioflavins). The combined extracts wereevaporated to dryness. For styrylbenzenes the residues were dissolved in100 μL of EtOH and purified by HPLC using a reverse phase column (Watersubondpad, 3.9×300 mm) with an isocratic solvent of 65% acetonitrile-35%trifluoroacetic acid (0.1%) in a flow rate of 0.8 mL/min. Thioflavinswere purified on a C4 column (Phenomenex Inc., Torrance, Calif.) elutedwith an isocratic solvent of 80% acetonitrile-20% 3,3-dimethyl-glutaricacid (5 mM, pH 7.0) in a flow rate of 0.8 mL/min. The desired fractionscontaining the product were collected, condensed and re-extracted withethylacetate. The no-carrier-added products were evaporated to drynessand re-dissolved in 100% EtOH (1 μCi/μL), The final ¹²⁵I 18, with aspecific activity of 2,200 Ci/mmole and a greater than 95% radiochemicalpurity, were stored at −20° C. up to 6 weeks for in vitro binding andautoradiography studies.

EXAMPLE 5 Partition Coefficient Determination

[0159] Partition coefficients were measured by mixing the [¹²⁵I]tracerwith 3 g each of 1-octanol and buffer (0.1 M phosphate, pH 7.4) in atest tube. The test tube was vortexed for 3 min at room temperature,followed by centrifugation for 5 min. Two weighed samples (0.5 g each)from the 1-octanol and buffer layers were counted in a well counter. Thepartition coefficient was determined by calculating the ratio of cpm/gof 1-octanol to that of buffer. Samples from the 1-octanol layer werere-partitioned until consistent partitions of coefficient values wereobtained. The measurement was done in triplicate and repeated threetimes.

EXAMPLE 6 Binding Assays Using Aggregated Aβ(1-40) or Aβ(1-42) peptidein solution

[0160] The solid forms of peptides Aβ(1-40) and Aβ(1-42) were purchasedfrom Bachem (King of Prussia, Pa.). Aggregation of peptides were carriedout by gently dissolving the peptide [0.5 mg/mL for Aβ(1-40) and 0.25mg/mL for Aβ (1-42) in a buffer solution (pH 7.4) containing 10 mMsodium phosphate and 1 mM EDTA. The solutions were incubated at 37° C.for 36-42 h with gentle and constant shaking. Binding studies werecarried out in 12×75 mm borosilicate glass tubes according to theprocedure described with some modifications (Klunk, W. E., et al., Biol.Psychiatry 35:627 (1994)). Aggregated fibrils (10-50 nM in the finalassay mixture) were added to the mixture containing 50 ml ofradioligands (0.01-0.5 nM) in 40% EtOH and 10% EtOH in a final volume of1 mL for saturation studies. Nonspecific binding was defined in thepresence of 2 mM thioflavin T for thioflavins. For inhibition studies, 1mL of the reaction mixture contained 40 ml of inhibitors (10-5-10-10 Min 10% EtOH) and 0.05 nM radiotracer in 40% EtOH. The mixture wasincubated at room temperature for 3 h and the bound and the freeradioactivity were separated by vacuum filtration through Whatman GF/Bfilters using a Brandel M-24R cell harvester followed by 2×3 mL washesof 10% ethanol at room temperature. Filters containing the bound I-125ligand were counted in a gamma counter (Packard 5000) with 70% countingefficiency. The results of saturation and inhibition experiments weresubjected to nonlinear regression analysis using software EBDA52 bywhich K_(d) and K_(i) values were calculated. Additional K_(i) valuesfor compounds of the invention are provided in FIG. 1A and FIG. 1B.TABLE 1 Inhibition constants (K_(i), nM) of compounds on ligand bindingto aggregates of Aβ(1-40) and Aβ(1-42) at 25° C. Aggregates of AβAggregates of Aβ (1-40) (1-42) Compounds vs[¹²⁵I]3 vs[¹²⁵I]3 ChrysamineG >1,000 >2,000 Thioflavin T 116 ± 20  294 ± 40  1 1.9 ± 0.3 0.8 ± 0.3 41.6 ± 0.5 5.0 ± 0.8 3 0.9 ± 0.2 2.2 ± 0.4 6a 5.4 ± 0.7 6.4 ± 0.7

[0161] Values are the mean±SEM of three independent experiments, each induplicates.

EXAMPLE 7 In Vivo Biodistribution of New Probes in Normal Mice

[0162] While under ether anesthesia, 0.15 mL of a saline solutioncontaining labeled agents (5-10 mCi) was injected directly into the tailvein of ICR mice (2-3 month-old, average weight 20-30 g). The mice weresacrificed by cardiac excision at various time points post injection.The organs of interest were removed and weighed, and the radioactivitywas counted with an automatic gamma counter (Packard 5000). Thepercentage dose per organ was calculated by a comparison of the tissuecounts to suitably diluted aliquots of the injected material. Totalactivities of blood and muscle were calculated under the assumption thatthey were 7% and 40% of the total body weight, respectively. TABLE 2Organ 2 min 30 min 60 min 6 h 24 h [¹²⁵I] Compound 3 (PC = 70) Blood15.74 ± 6.06  3.26 ± 0.05 3.79 ± 0.19 1.44 ± 0.05 0.29 ± 0.09 Heart 1.79± 0.39 0.20 ± 0.01 0.17 ± 0.02 0.05 ± 0.01 0.01 ± 0.00 Liver 31.62 ±2.38  10.93 ± 2.34  9.21 ± 3.05 1.52 ± 0.30 0.30 ± 0.07 Brain 0.67 ±0.11 0.97 ± 0.29 1.57 ± 0.24 0.65 ± 0.11 0.04 ± 0.01 [¹²⁵I] Compound 6a(PC = 312) Blood 8.02 ± 0.82 5.15 ± 0.23 4.16 ± 0.28 1.49 ± 0.26 0.41 ±0.09 Heart 2.19 ± 0.43 0.69 ± 0.02 0.66 ± 0.06 0.22 ± 0.06 0.08 ± 0.01Liver 28.84 ± 3.77  21.22 ± 5.86  17.20 ± 2.49  5.79 ± 1.24 3.05 ± 0.87Brain 1.50 ± 0.10 1.59 ± 0.19 1.89 ± 0.43 1.08 ± 0.08 0.91 ± 0.08 [¹²⁵I]Compound 8 (PC = 124) Blood 4.31 ± 0.34 2.80 ± 0.45 2.94 ± 0.18 2.23 ±0.53 1.68 ± 0.56 Heart 1.20 ± 0.18 0.19 ± 0.05 0.11 ± 0.02 0.05 ± 0.000.02 ± 0.00 Liver 25.04 ± 2.45  17.45 ± 2.01  5.57 ± 0.39 1.08 ± 0.110.42 ± 0.08 Brain 1.43 ± 0.23 2.08 ± 0.03 1.26 ± 0.10 0.12 ± 0.02 0.01 ±0.00 Organ 2 min 30 min 1 hr 2 hr 6 hr 24 hr [¹²⁵I]Compound 19 (PC =100) BLOOD 6.41 ± 0.77 2.44 ± 0.36 2.50 ± 0.11 1.82 ± 0.21 1.40 ± 0.270.18 ± 0.02 HEART 0.79 ± 0.14 0.16 ± 0.02 0.12 ± 0.02 0.08 ± 0.01 0.04 ±0.01 0.01 ± 0.00 MUSCLE 13.81 ± 3.44  6.08 ± 0.59 5.03 ± 1.03 2.96 ±0.84 1.46 ± 0.42 0.27 ± 0.11 LUNG 1.56 ± 0.33 0.31 ± 0.07 0.34 ± 0.080.20 ± 0.05 0.12 ± 0.05 0.05 ± 0.03 KIDNEY 4.75 ± 0.49 1.51 ± 0.27 1.17± 0.29 0.53 ± 0.05 0.25 ± 0.05 0.05 ± 0.01 SPLEEN 0.40 ± 0.06 0.09 ±0.02 0.08 ± 0.01 0.05 ± 0.01 0.04 ± 0.01 0.01 ± 0.00 LIVER 20.88 ± 2.63 6.32 ± 0.55 5.88 ± 0.85 2.90 ± 0.21 1.54 ± 0.08 0.61 ± 0.11 SKIN 5.72 ±0.90 4.69 ± 1.06 4.28 ± 0.25 3.14 ± 0.51 2.19 ± 0.63 0.22 ± 0.06 BRAIN2.88 ± 0.25 0.26 ± 0.00 0.21 ± 0.03 0.14 ± 0.03 0.06 ± 0.02 0.02 ± 0.00

[0163] Having now fully described this invention, it will be understoodto those of ordinary skill in the art that the same can be performedwithin a wide and equivalent range of conditions, formulations, andother parameters without affecting the scope of the invention or anyembodiment thereof. All patents, patent applications, and publicationscited herein are fully incorporated by reference herein in theirentirety.

What is claimed is:
 1. A pharmaceutical composition, comprising acompound of Formula III′ and a pharmaceutically acceptable excipient ordiluent, wherein a compound of Formula III′ is selected from:

or a pharmaceutically acceptable salt thereof, wherein A, B and D are CHor N, provided that no more than two of A, B and D is N; R³ is Br, I, F,¹²⁵I, ¹³¹I, ¹²³I, ¹⁸F, ⁷⁶Br, ⁷⁷Br, haloalkyl, Sn(alkyl)₃ or -L-Ch; R¹and R² are independently hydrogen, C₁₋₄ alkyl, C₂₋₄ aminoalkyl, C₁₋₄haloalkyl, haloarylalkyl, -L-Ch, or R¹ and R² are taken together withthe nitrogen to which they are attached to form a 5- to 7-memberheterocyclic ring optionally having O, S or NR⁵ in said ring, where R⁵is hydrogen or C₁₋₄ alkyl; L is a covalent bond or linking group, suchas —(CH₂)_(n)—, or —(CH₂)_(n)—C(O)— where n is 0-5; and Ch is atetradentate ligand capable of complexing with a metal; with the provisothat only one of R¹, R² and R³ can be -L-Ch.
 2. A pharmaceuticalcomposition of claim 1, wherein A and B are CH; and D is N.
 3. Apharmaceutical composition of claim 1, wherein A and D are CH; and B isN.
 4. A pharmaceutical composition of claim 1, wherein B and D are CH;and A is N.
 5. A pharmaceutical composition of claim 2, wherein R¹ andR² are independently hydrogen or C₁₋₄ alkyl.
 6. A pharmaceuticalcomposition of claim 5, wherein R¹ and R² are both methyl.
 7. Apharmaceutical composition of claim 6, wherein R³ is Br, I, F, ¹²⁵I,¹³¹I, ¹²³I, ¹⁸F, ⁷⁶Br, ⁷⁷Br, ¹⁸F/fluoro(C₁₋₅)alkyl or Sn(alkyl)₃.
 8. Apharmaceutical composition of claim 7, wherein R³ is ¹⁸F/fluoromethyl,¹⁸F/fluoroethyl, ¹⁸F/fluoropropyl, ¹⁸F/fluorobutyl, or ¹⁸F/fluoropentyl.9. A pharmaceutical composition of claim 2, wherein R³ is L-Ch.
 10. Apharmaceutical composition of claim 9, wherein Ch is selected from thegroup consisting of:


11. A pharmaceutical composition of claim 10, wherein Ch is:


12. A pharmaceutical composition of claim 11, wherein R¹ and R² areindependently hydrogen or C₁₋₄ alkyl.
 13. A pharmaceutical compositionof claim 12, wherein R¹ and R² are both methyl.
 14. A diagnosticcomposition for imaging amyloid deposits, comprising a radiolabeledcompound of Formula III′, wherein a radiolabeled compound of FormulaIII′ is selected from:

or a pharmaceutically acceptable salt thereof, wherein A, B and D are CHor N, provided that no more than two of A, B and D is N; R³ is ¹²⁵I,¹³¹, ¹²³I, ¹⁸F, ⁷⁶Br, ⁷⁷Br, ¹⁸F(C₁₋₅)alkyl or -L-Ch; R¹ and R² areindependently hydrogen, C₁₋₄ alkyl, C₂₋₄ aminoalkyl, C₁₋₄ haloalkyl,haloarylalkyl, -L-Ch, or R¹ and R² are taken together with the nitrogento which they are attached to form a 5- to 7-member heterocyclic ringoptionally having O, S or NR⁵ in said ring, where R⁵ is hydrogen or C₁₋₄alkyl; L is a covalent bond or linking group, such as —(CH₂)_(n)—, or—(CH₂)_(n)—C(O)— where n is 0-5; and Ch is a tetradentate ligandcomplexed with a radiolabeled metal; with the proviso that only one ofR¹, R² and R³ can be -L-Ch.
 15. A method of inhibiting amyloid plaqueaggregation in a mammal, comprising administering a composition of claim1 in an amount effective to inhibit amyloid plaque aggregation.
 16. Amethod of imaging amyloid deposits, comprising: a. introducing into amammal a detectable quantity of a diagnostic composition of claim 14;and b. allowing sufficient time for the labeled compound to becomeassociated with amyloid deposits; and c. detecting the labeled compoundassociated with one or more amyloid deposits.